minocycline and Jaundice--Neonatal

Hazardous levels of bilirubin produce oxidative stress in vitro and may play a role in the genesis of bilirubin-induced neurologic dysfunction (BIND). We hypothesized that the antioxidants taurourosdeoxycholic acid (TUDCA), 12S-hydroxy-1,12-pyrazolinominocycline (PMIN), and minocycline (MNC) inhibit oxidative stress and block BIND in hyperbilirubinemic j/j Gunn rat pups that were given sulfadimethoxine to induce bilirubin encephalopathy.. At peak postnatal hyperbilirubinemia, j/j Gunn rat pups were dosed with sulfadimethoxine to induce bilirubin encephalopathy. Pups were given TUDCA, PMIN, MNC, or vehicle pretreatment (15 min before sulfadimethoxine). After 24 h, BIND was scored by using a rating scale of neurobehavior and cerebellar tissue 4-hydroxynonenal and protein carbonyl dinitrophenyl content were determined. Nonjaundiced heterozygous N/j pups served as controls.. Administration of sulfadimethoxine induced BIND and lipid peroxidation but not protein oxidation in hyperbilirubinemic j/j pups. TUDCA, PMIN, and MNC each reduced lipid peroxidation to basal levels observed in nonjaundiced N/j controls, but only MNC prevented BIND.. These findings show that lipid peroxidation inhibition alone is not sufficient to prevent BIND. We speculate that the neuroprotective efficacy of MNC against BIND involves action(s) independent of, or in addition to, its antioxidant effects.

Topics: Aldehydes; Animals; Animals, Newborn; Antioxidants; Behavior, Animal; Bilirubin; Cerebellum; Disease Models, Animal; Humans; Infant, Newborn; Jaundice, Neonatal; Kernicterus; Lipid Peroxidation; Minocycline; Motor Activity; Neuroprotective Agents; Oxidative Stress; Protein Carbonylation; Pyrazoles; Rats; Rats, Gunn; Sulfadimethoxine; Taurochenodeoxycholic Acid; Time Factors

Encephalopathy induced by hyperbilirubinemia in infants has been described in the medical literature for over a century but neither the cellular nor molecular mechanisms underlying bilirubin neurotoxicity are well understood. In this study, we have demonstrated that minocycline potently protects primary cultured rat cerebellar granule neurons against bilirubin neurotoxicity (IC50 approximately 2 microm) and almost completely blocks cerebellar hypoplasia and the profound loss of Purkinje and granule neurons observed in homozygous Gunn rats, a genetic model of hyperbilirubinemia-induced neurotoxicity. Minocycline-treated newborn Gunn rats had nearly equivalent numbers of viable Purkinje and granule neurons in the cerebellum as did control animals. Moreover, minocycline inhibits the bilirubin-induced phosphorylation of p38 mitogen-activated protein kinase both in vivo as well as in vitro. Taken together our data demonstrate that minocycline is able to greatly reduce bilirubin-induced neurotoxicity and suggest that minocycline's neuroprotective effects may be due in part to an inhibition of p38 mitogen-activated protein kinase activity. Our findings may lead to novel approaches for treating bilirubin-induced encephalopathy.

Topics: Animals; Anti-Bacterial Agents; Cells, Cultured; Cerebellar Cortex; Disease Models, Animal; Down-Regulation; Enzyme Inhibitors; Homozygote; Humans; Infant, Newborn; Jaundice, Neonatal; Kernicterus; Minocycline; Nerve Degeneration; Neuroprotective Agents; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Purkinje Cells; Rats; Rats, Gunn